The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. ISS can be defined as a condition characterized by a height more than 2 standard deviations below the corresponding average height for a given age, sex and population, without findings of disease. Approximately 80% of all children referred for short stature will be labeled as ISS. ISS can be considered as part of the continuum extending from complete growth hormone deficiency (GHD) to normality and covering different degrees of GH secretion and responsiveness.
ISS has recently been subdivided into two major groups: a) familial short stature (FSS), when the child is short compared with the reference population, but remains within the range of target height; b) non-familial short stature (NFSS), when the child is short both in comparison with the reference population and the target height. This latter subgroup inevitably includes short children with constitutional delay of growth and puberty (CDGP).
Currently, the only approved therapy for ISS is recombinant human growth hormone therapy. Individual patient responsiveness to growth hormone is quite variable with some patients receiving no benefit in terms of increased growth velocity. By definition, these patients have normal growth hormone secretion but have a limitation in their growth response to both endogenous and exogenous growth hormone. Alternative therapies which seek to improve the downstream growth hormone signaling pathway are needed. Additionally, growth hormone is approved for patients born small for gestational age with lack of catch up growth. These patients are also variably responsive to growth hormone therapy and are in need of additional therapeutic options. Thus, while a significant percentage of the population suffers from ISS or other conditions that result in short stature, there are currently limited tools to identify candidates that are likely to be successfully treated for short stature using specific treatments, and limited treatments available for individuals suffering from ISS or short stature of known causes. The instant disclosure seeks to address one or more needs in the art.